Growth Inhibition of Human Glioma Cells Induced by 8-Chloroadenosine, an Active Metabolite of 8-Chloro Cyclic Adenosine 3′:5′-Monophosphate

Chloroadenosine 3':5'-monophosphate (SClcAMP) inhibits the growth of human glioma cell lines at much lower concentrations than more commonly used cyclic AMP analogues, without inducing morpho logical differentiation. The mechanism by which SClcAMP exerts this effect is not fully understood. We examined whether the growth-inhib itory effect of this compound is due to an active metabolite, using a sulforhodamine protein stain assay to determine the proliferation rate of the WF human glioma cell line. 8-Chloroadenosine, one of the metab olites, inhibited the proliferation of WF human glioma cells more po tently than SClcAMP. In the presence of adenosine deaminase, which converts 8-chloroadenosine into 8-chloroinosine, 8-chloroadenosine no longer inhibited human glioma cell growth. Addition of adenosine deam inase also largely reduced the growth-inhibitory effect of SClcAMP, but not of 8-(4-chlorophenylthio)cAMP. High performance liquid chroma- tography analysis revealed that at least part of the SClcAMP in the culture medium is converted into 8-chloroadenosine. We concluded that SClcAMP exerts its growth-inhibitory effect through its active metab olite 8-chloroadenosine. Adenylate cyclase assays showed that 8-chlo roadenosine does not affect the intracellular cAMP production through adenosine A, or A, receptor activation, which makes it unlikely that 8-chloroadenosine inhibits glioma cell growth by increasing the intra cellular cyclic AMP concentration.